Systems and method for delivery of therapeutic gas to patients, in need thereof, receiving breathing gas from a ventilator that varies at least pressure and/or flow using enhanced therapeutic gas (no) flow measurement

ABSTRACT

The present disclosure generally relates to systems and methods for delivery of therapeutic gas to patients, in need thereof, receiving breathing gas from a high frequency ventilator using at least enhanced therapeutic gas (e.g., nitric oxide, NO, etc.) flow measurement. At least some of these enhanced therapeutic gas flow measurements can be used to address some surprising phenomenon that may, at times, occur when wild stream blending therapeutic gas into breathing gas a patient receives from a breathing circuit affiliated with a high frequency ventilator. Utilizing at least some of these enhanced therapeutic gas flow measurements the dose of therapeutic gas wild stream blended into breathing gas that the patient receives can at least be more accurate and/or under delivery of therapeutic gas into the breathing gas can be avoided and/or reduced.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.17/078,821, filed Oct. 23, 2020 which is a continuation of U.S.application Ser. No. 16/058,402, filed Aug. 8, 2018 which is acontinuation of U.S. application Ser. No. 14/700,594, filed Apr. 30,2015, which claims priority to U.S. Provisional application no.61/987,852, filed May 2, 2014, each of which are hereby incorporated byreference in their entirety.

FIELD

The present invention generally relates to systems and methods fordelivery of therapeutic gas to patients, in need thereof, receivingbreathing gas from a ventilator that varies at least pressure and/orflow using enhanced therapeutic gas (NO) flow measurement.

BACKGROUND

Therapeutic gas can be delivered to patients, in need thereof, toprovide medical benefits. One such therapeutic gas is nitric oxide (NO)gas that, when inhaled, acts to dilate blood vessels in the lungs,improving oxygenation of the blood and reducing pulmonary hypertension.Because of at least this, nitric oxide can be provided as a therapeuticgas in the inspiratory breathing gases for patients with pulmonaryhypertension.

Further, many patients receive breathing gas (e.g., inspiratorybreathing gas) from a ventilator that can at least vary pressure and/orflow (e.g., high frequency ventilator, etc.). Unlike conventionalventilators, high frequency ventilators use a constant distendingpressure (mean airway pressure [MAP]) with pressure variationsoscillating around the MAP at very high rates (e.g., up to 900 cyclesper minute, etc.). In other words, high frequency ventilators maintain aconstant pressure within the patient breathing circuit and this pressureoscillates at very high rates. Beneficially, this can encourage gasexchange across blood vessels in the patient's lungs.

Although high frequency ventilators can be beneficial, patientsreceiving breathing gas from high frequency ventilators may receiveadditional benefits from therapeutic gas. To take advantage of theseadditional benefits the therapeutic gas may need to be delivered intobreathing gas that the patient receives from a breathing circuitaffiliated with the high frequency ventilator. However, deliveringtherapeutic gas into patient breathing gas being delivered to a patientfrom a high frequency ventilator can be difficult and/or presentunforeseen problems. These difficulties and/or unforeseen problems canimpact the accuracy of therapeutic gas delivery and/or dosing.

Accordingly, a need exists to overcome the difficulties and/orunforeseen problems that can occur when delivering therapeutic gas to apatient receiving breathing gas from a ventilator that can at least varypressure and/or flow (e.g., high frequency ventilator, etc.) to increaseaccuracy of therapeutic gas delivery and/or dosing.

SUMMARY

Aspects of the present invention relate to a nitric oxide deliverysystem for delivering therapeutic gas comprising NO into the inspiratorylimb of a breathing circuit, which may be affiliated with a highfrequency ventilator. The nitric oxide delivery system may comprise aninjector module for receiving a flow of therapeutic gas and injectingthe therapeutic gas into the delivery circuit. The injector module mayinclude and/or can be in communication with a mono-directional NO flowsensor capable of measuring forward NO flow (e.g., going into theinjector module, from the nitric oxide delivery system to the injectormodule, etc.) and/or a bi-directional NO flow sensor capable ofmeasuring forward NO flow and reverse NO flow. Using the above flowsensor and/or information communicated from the flow sensor to thenitric oxide delivery system, the nitric oxide delivery system candeliver NO to the injector module more accurately and/or under deliveryof therapeutic gas into the breathing gas can be avoided and/or reduced.

In exemplary embodiments, the NO flow sensor can be used to address atleast false flow phenomena surprisingly found by applicant.

In exemplary embodiments, the flow information can be from thebi-directional flow sensor. This information from the bi-directional NOflow sensor can be used to detect use of a ventilator that can at leastvary pressure and/or flow (e.g., high frequency ventilator, etc.) and/orcompensate for distortions in the flow information generated by at leastthe ventilator.

In exemplary embodiments, the flow information can be from themono-directional flow sensor. This information from the mono-directionalflow sensor can be used to detect use of a ventilator that can at leastvary pressure and/or flow (e.g., high frequency ventilator, etc.) and/orcompensate for distortions in the flow information generated by at leastthe ventilator.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the present invention will be more fullyunderstood with reference to the following, detailed description whentaken in conjunction with the accompanying figures, wherein:

FIG. 1 illustratively depicts an exemplary nitric oxide delivery system,in accordance with exemplary embodiments of the present invention;

FIG. 2 illustratively depicts an exemplary nitric oxide delivery systemincluding a check valve, in accordance with exemplary embodiments of thepresent invention;

FIG. 3 illustratively depicts an exemplary nitric oxide delivery systemused with an exemplary ventilator that includes a free breathing valve,in accordance with exemplary embodiments of the present invention;

FIGS. 4A-4B illustratively depict an exemplary injector module thatincludes a bi-directional NO flow sensor, in accordance with exemplaryembodiments of the present invention;

FIGS. 5A-5C illustratively depict exemplary graphical representations ofinformation from flow sensors, in accordance with exemplary embodimentsof the present invention; and

FIGS. 6A-6C illustratively depict exemplary graphical representations ofinformation from flow sensors that include information and/orrepresentations indicative of negative flow, in accordance withexemplary embodiments of the present invention.

DETAILED DESCRIPTION

The present invention generally relates to systems and methods fordelivery of therapeutic gas to patients, in need thereof, receivingbreathing gas from a ventilator that can at least vary pressure and/orflow (e.g., high frequency ventilator, etc.) using, amongst otherthings, enhanced therapeutic gas (e.g., nitric oxide, NO, etc.) flowmeasurement. At least some of these enhanced therapeutic gas flowmeasurements can be used to address some surprising phenomenon that may,at times, occur when wild stream blending therapeutic gas into breathinggas that a patient receives from a breathing circuit affiliated with aventilator that can at least vary pressure and/or flow (e.g., highfrequency ventilator, etc.). Utilizing at least some of these enhancedtherapeutic gas flow measurements and/or inventions herein the dose oftherapeutic gas wild stream blended into breathing gas that the patientreceives from the ventilator can be more accurate and/or under deliveryof therapeutic gas into the breathing gas can be avoided and/or reduced.

As used herein, “wild stream blended proportional”, “wild streamblending”, “ratio metric blending” and the like, relates to streamblending, where the main flow stream is an uncontrolled (unregulated)stream that is referred to as the wild stream, and the component beingintroduced into the wild stream is controlled as a proportion of themain stream, which may typically be blended upstream (or alternativelydownstream) of the main stream flowmeter. In various embodiments, theinspiratory flow may be the “wild stream” as the flow is notspecifically regulated or controlled, and the nitric oxide is the blendcomponent that is delivered as a percentage of the inspiratory flowthrough a delivery line.

As used herein, the term “false NO flow” and the like refers to flowphenomena that is inaccurately measured by flow sensors. Examples ofsuch false NO flow include, but are not limited to, the measurement ofNO flow by a flow sensor when NO is not actually flowing and themeasurement of NO flow that is a significantly different value than theactual NO flow.

Systems and methods of the present invention can deliver therapeutic gasto a patient from a delivery system to an injector module, which in turncan be in fluid communication with a breathing circuit (affiliated witha ventilator such as, but not limited to, a high frequency ventilatorand/or any other applicable ventilator and/or ventilation techniques)that the patient receives breathing gas from. Systems and methods of thepresent invention can include at least one therapeutic gas flow sensorthat can measure the flow of therapeutic gas from the delivery system tothe injector module, and in turn into the breathing circuit and to thepatient. Advantageously, the therapeutic gas flow sensor can measureflow in more than one direction (e.g., bi-directional therapeutic gasflow sensor) and/or address some of the surprising phenomena that may,at times, occur when wild stream blending therapeutic gas into breathinggas in a breathing circuit affiliated with a ventilator that can atleast vary pressure and/or flow (e.g., high frequency ventilator, etc.).

Further, systems and methods of the present invention can use techniques(e.g., algorithms, user input, etc.) to determine whether a ventilatorthat can at least vary pressure and/or flow (e.g., high frequencyventilator, etc.) may be being used and/or to compensate for at leastsome of the surprising phenomena that may, at times, occur when wildstream blending therapeutic gas into breathing gas in a breathingcircuit affiliated with the ventilator. These techniques can, at times,use information from at least the therapeutic gas flow sensor that maymeasure flow in one direction (e.g., mono-directional flow sensor)and/or in more than one direction (e.g., bi-directional flow sensor).

Further still, systems and methods of the present invention can usetechniques (e.g., algorithms, user input, etc.) to more effectivelyactuate valves and/or compensate for forces that may affect valveactuation such as, but not limited to, static friction, dynamicfriction, and/or valve component interactions, to name a few. This can,in at least some instances, result in increased accuracy of NO deliveryand monitoring and/or under delivery of therapeutic gas into thebreathing gas can be avoided and/or reduced.

Referring to FIG. 1 , illustratively depicted is an exemplary nitricoxide delivery system 100 for delivering therapeutic nitric oxide gas,via an injector module, to a patient receiving breathing gas from a highfrequency ventilator. It will be understood that any teachings of thepresent invention can be used in any applicable system for deliveringtherapeutic gas to a patient receiving breathing gas from a breathingapparatus (e.g., ventilator, high frequency ventilator, breathing mask,nasal cannula, etc.). For example, systems and methods of the presentinvention can use, modify, and/or be affiliated with the deliverysystems and/or other teachings of U.S. Pat. No. 5,558,083 entitled“Nitric Oxide Delivery System”, the contents of which is incorporatedherein by reference in its entirety.

Systems and methods of the present invention at times refer to use witha high frequency ventilator; however, systems and methods of the presentinvention can be used with any applicable breathing apparatus that maybe affiliated with high frequency ventilation, any applicable breathingapparatus that may encounter like difficulties and/or problems, and/orany applicable breathing apparatus affiliated with ventilators and/orventilation techniques (e.g., bi-level positive airway pressure, anyventilation technique varying pressure and/or flow, etc.) that canprovide reverse inspiratory pressure and/or flow. Accordingly, referenceto a high frequency ventilator is merely for ease and is in no way meantto be a limitation. Further, at times, inspiratory pressure and/or flowmay not be reverse, rather there may be varying pressure and/or flow(e.g., high frequency sinusoidal pressure and/or flow) that can remainpositive. For ease, reference made to reverse inspiratory pressureand/or flow, at times, encompasses situations when varying pressureand/or flow (e.g., high frequency sinusoidal pressure and/or flow) thatcan remain positive. Accordingly reference to reverse inspiratorypressure and/or flow is merely for ease and is in no way meant to be alimitation.

Systems and method of the present invention can be for use with anyapplicable therapeutic gas. The therapeutic gas, therapeutic gas flowmeasurements, therapeutic gas delivery system, and the like are, attimes, described with reference to nitric oxide gas (NO) used forinhaled nitric oxide gas therapy. It will be understood that othertherapeutic gases can be used. Accordingly, reference to nitric oxide,NO, and the like is merely for ease and is in no way meant to be alimitation.

Systems and methods of the present invention can be used to wild streamblend therapeutic gas into patient breathing gas in a breathing circuitand/or at any location. By way of example, therapeutic gas can be wildstream blended into patient breathing gas at a location prior to thebreathing circuit. By way of another example, in at least someinstances, the patient breathing circuit can include only one limb forboth inspiratory and expiratory flow. For example, BiPAP ventilators canhave only one limb that combines the inspiratory limb and expiratorylimb. Following this example, therapeutic gas can be wild stream blendedinto patient breathing gas in the on limb that acts as both theinspiratory limb and expiratory limb. For ease, patient breathingcircuits are, at times, depicted as having a separate inspiratory limband expiratory limb. This is merely for ease and is in no way meant tobe a limitation.

In exemplary embodiments, nitric oxide delivery systems such as nitricoxide delivery system 100 can be used to wild stream blend therapeuticgas (e.g., nitric oxide, NO, etc.) into patient breathing gas in abreathing circuit (affiliated with a high frequency ventilator) as aproportion of the patient breathing gas (e.g., ppm, etc.) and/or as apulse (e.g., ml/breath, mg/kg/hr, etc.) To at least wild stream blend NOor pulse NO (e.g., which may also be wild stream blended as a pulse,etc.) into patient breathing gas, nitric oxide delivery system 100 caninclude and/or receive nitric oxide from a nitric oxide source 103(e.g., cylinder storing NO, NO generator, etc.) for example, via aconduit 105. Instead of a cylinder of NO-containing gas, the NO may begenerated bedside, such as by an appropriate chemical reaction, e.g. thereaction of a NO-releasing agent such as nitrogen dioxide with areductant such as ascorbic acid. Further, conduit 105 can also be influid communication with an injector module 107, for example, via atherapeutic gas inlet 110, and injector module 107 can also be in fluidcommunication with an inspiratory limb of a breathing circuit affiliatedwith a high frequency ventilator 117.

As shown, high frequency ventilator 117 can include an inspiratoryoutlet for delivering breathing gas (e.g., forward flow 133) to thepatient via an inspiratory limb 121 of a patient breathing circuit andan expiratory inlet for receiving patient expiration via an expiratorylimb 127 of the patient breathing circuit. With injector module 107coupled to inspiratory limb 121 of the breathing circuit, nitric oxidecan be delivered from nitric oxide delivery system 100 (e.g., NO forwardflow 137) to injector module 107, via conduit 105 and/or therapeutic gasinlet 110. This nitric oxide can then be delivered, via injector module107, into inspiratory limb 121 of the patient breathing circuitaffiliated high frequency ventilator 117 being used to deliverybreathing gas to a patient 108.

To regulate flow of nitric oxide through conduit 105 to injector module107, and in turn to a patient 108 receiving breathing gas from thepatient breathing circuit, nitric oxide delivery system 100 can includeone or more control valves 109 (e.g., proportional valves, binaryvalves, etc.). For example, with control valve 109 open, nitric oxidecan be delivered to patient 108 by flowing in a forward direction (e.g.,NO forward flow 137) through conduit 105 to injector module 107, and inturn to patient 108. For another example, with control valve 109 closed,nitric oxide may not be delivered to patient 108 as it may not flow in aforward direction.

In at least some instances, nitric oxide delivery system 100 can includeone or more NO flow sensors 115 that can measure the flow of therapeuticgas (e.g., NO forward flow 137) through control valve 109 and/or conduit105, in turn enabling measurement of the flow of therapeutic gas througha therapeutic gas inlet 110 into injector module 107, and in turn topatient 108. Further, in at least some instances, injector module 107can include one or more breathing circuit gas (BCG) flow sensors 119that can measure the flow of at least patient breathing gas (e.g.,forward flow 133) through injector module 107, and in turn to patient108. Although shown as being within injector module 107, BCG flow sensor119 can be placed elsewhere in the inspiratory limb 121, such asupstream of the injector module 107. Also, instead of receiving flowinformation from BCG flow sensor 119, nitric oxide delivery system 100may receive flow information directly from the high frequency ventilator117 indicating the flow of breathing gas from high frequency ventilator117.

In exemplary embodiments, systems and methods of the present inventioncan use, modify, and/or be affiliated with therapeutic gas deliverysystems and methods which may have bi-directional breathing circuit gas(BCG) flow sensors. By way of example, the one or more breathing circuitgas (BCG) flow sensors 119 described herein may be bi-directional and/orsystems and methods of the present invention can further include one ormore bi-directional breathing circuit gas (BCG) flow sensors. Forexample, systems and methods of the present invention can use, modify,and/or be affiliated with the delivery systems and/or other teachings ofU.S. patent application Ser. No. 14/672,447, filed Mar. 30, 2015 andentitled “SYSTEMS AND METHOD FOR DELIVERY OF THERAPEUTIC GAS TO PATIENTSIN NEED THEREOF USING ENHANCED BREATHING CIRCUIT GAS (BCG) FLOWMEASUREMENT”, the contents of which is incorporated herein by referencein its entirety.

In exemplary embodiments, nitric oxide gas flow can be proportional(also known as ratio-metric) to the breathing gas flow to provide adesired concentration of NO in the combined breathing gas andtherapeutic gas. For example, nitric oxide delivery system 100 canconfirm that the desired concentration of NO is in the combinedbreathing gas and therapeutic gas by using the known NO concentration ofNO source 103; the amount of breathing gas flow in the patient circuitusing information from BCG flow sensor 119; and the amount oftherapeutic gas flow in conduit 105 to injector module 107 (and in turnto patient 108) using information from NO flow sensor 115.

To at least deliver therapeutic gas to a patient and/or perform at leastsome teachings disclosed herein nitric oxide delivery system 100 caninclude a control system that can include one or more CPUs 111. CPU 111can be coupled to a memory (not shown) and may be one or more of readilyavailable memory such as random access memory (RAM), read only memory(ROM), flash memory, compact disc, floppy disk, hard disk, or any otherform of local or remote digital storage. Support circuits (not shown)can be coupled to CPU 111 to support CPU 111, sensors, valves, samplingsystems, user inputs/displays, injector modules, breathing apparatus,etc. in a conventional manner. These circuits can include cache, powersupplies, clock circuits, input/output circuitry, subsystems, powercontrollers, signal conditioners, and the like. CPU 111 can be incommunication with sensors, valves, sampling systems, userinputs/displays, injector modules, breathing apparatus, etc. Inexemplary embodiments, the memory may store a set of machine-executableinstructions (or algorithms), when executed by CPU 111, that can causethe delivery system to perform a method. For example, the deliverysystem can perform a method comprising: measuring flow in theinspiratory limb of a patient breathing circuit, delivering therapeuticgas containing nitric oxide to the patient during inspiratory flow,monitoring inspiratory flow or changes in the inspiratory flow, andvarying the quantity (e.g. volume or mass) of therapeutic gas deliveredin a subsequent inspiratory flow. The machine-executable instructionsmay also comprise instructions for any of the other methods describedherein.

Further, to at least ensure accurate dosing of the therapeutic gas,nitric oxide delivery system 100 can include a user input/display 113that can include a display and a keyboard and/or buttons, or may be atouchscreen device. User input/display 113 can receive desired settingsfrom the user, such as the patient's prescription (in mg/kg ideal bodyweight, mg/kg/hr, mg/kg/breath, mL/breath, cylinder concentration,delivery concentration, duration, etc.), the patient's age, height, sex,weight, etc. User input/display 113 may also receive user inputregarding the mode of operation, such as the use with a high frequencyventilator. For example, the user input/display 113 may have a button orother means for the user to indicate that the nitric oxide deliverydevice 100 is in use with a high frequency ventilator. Userinput/display 113 can in at least some instances be used to confirmpatient dosing and/or gas measurements, for example, using a gassampling system 129 that can receive samples of the gas being deliveredto patient 108 via a sample line 131. Gas sampling system 129 caninclude numerous sensors such as, but not limited to, a nitric oxide gassensor, a nitrogen dioxide gas sensor, and an oxygen gas sensor that canbe used to display relevant information (e.g., gas concentrations, etc.)on user input/display 113.

As shown in FIGS. 1-3 , the CPU 111 may be in communication with controlvalve 109, user input/display 113, NO flow sensor 115, BCG flow sensor119 and/or gas sampling system 129. The CPU 111 may implement any of themethods described herein through the use of appropriate algorithms.

Although the above can be used beneficially to deliver therapeutic gasto a patient receiving breathing gas from a patient breathing circuitaffiliated with a high frequency ventilator, the above can fail to takeinto account at least some surprising phenomena, for example, that mayoccur when wild stream blending NO into patient breathing gas as apercentage of the patient breathing gas. Without knowledge of at leastsome of these phenomena the actual NO concentration (e.g., NOconcentration of the patient breathing gas, parts per million (PPM) NO,etc.) can be different (e.g., under dosed, etc.) from the desired NOconcentration. This NO concentration can be particularly important as itcan be the dosage of treatment for a patient. Accordingly, by takinginto account at least some of these phenomena more accurate NO dosingcan be possible and/or under dosing of NO can be avoided and/or reduced.

Extensive study discovered a phenomenon (false NO flow phenomenon)where, it was surprisingly found that wild stream blending NO withpatient breathing gas in a breathing circuit affiliated with a highfrequency ventilator, in at least some instances, can cause NO flow inthe nitric oxide delivery line (e.g., conduit 105) and/or the injectormodule (e.g., therapeutic gas inlet 110) to be measured falsely asflowing by flow sensor 115 (even though NO may not be flowing). This canresult in reduced accuracy of NO delivery and/or monitoring, forexample, by NO delivery system 100 and/or this false NO flow can causeNO delivery system 100 to provide less NO than desired (e.g., underdose) as the system may falsely believe that the NO was provided.

These false NO flow measurements can be caused by vibrations or pressureoscillations caused by rapidly actuating valves and/or diaphragms (notshown) in high frequency ventilator 117 being registered as flow, forexample, by flow sensor 115, which in turn NO delivery system 100 mayuse for NO delivery and/or monitoring. Flow can be falsely registered byflow sensor 115 because these vibrations or pressure oscillations maypressurize NO gas contained in conduit 105 for brief periods of time andwhen substantially small amounts of NO flow through conduit 105 thispressurization and/or depressurization (at times referred to simply aspressurization for ease) can result in the appearance of flow (e.g., NOforward flow 137) on NO flow sensor 115. This can result in situationswhere the nitric oxide delivery system falsely detects that NO forwardflow 137 is occurring (e.g., in conduit 105, at injector module 107,through therapeutic gas inlet 110, etc.) when there may actually not beforward flow or flow at all. Accordingly, addressing at least this falseflow phenomenon can result in increased accuracy of NO delivery andmonitoring and/or under delivery of therapeutic gas into the breathinggas can be avoided and/or reduced.

Referring to FIG. 2 , in exemplary embodiments, addressing at leastfalse NO flow, a check valve 202 (e.g., a pneumatic check valve) can beplaced in fluid communication with inspiratory limb 121. For example,check valve 202 can be placed so it is in fluid communication withinspiratory limb 121, while not be located at inspiratory limb 121. Foranother example, check valve 202 can be placed at inspiratory limb 121upstream of injector module 107. In use, check valve 202 can open sosources of false NO flow, vibrations, and/or pressure oscillations canbe diverted prior to reaching injector module 107 and/or being measuredby flow sensor 115. Although the use of check valves can address atleast some of the issues affiliated with false NO flow, these checkvalves can also introduce numerous problems such as, but not limited to,response flow lag from forward flow cracking pressure, surface seal andmaterial electrostatic physical attraction to contamination affectingseal performance, unit to unit repeatability from component tolerance ormaterial choice, surface finish affecting seal performance,characterized as an un-damped spring mass system vulnerable to producingaudible noise or forward flow inducing oscillation “noise”, and/or candetract from the overall flow control accuracy, repeatability, andcontrol response time, to name a few.

Further, check valve 202 can interfere with high frequency ventilatorsthat include a free breathing valve 302 as illustrated in FIG. 3 . Freebreathing valve 302 (sometimes called an anti-suffocation valve) canopen to atmosphere should a patient using the ventilator spontaneouslybreath. Free breathing valve 302 can be required for ventilators toensure that a patient who attempts to spontaneously breathe has theability to inhale air. By way of example, if a ventilator does notinclude this free breathing valve it can be considered as a closedsystem with the ventilator being in control of when breathing air can bedelivered to the patient. Without this free breathing valve, if apatient attempts to spontaneously breathe the user can be unable to pullin air to breathe as there can be no entrance for air to flow into thepatient breathing circuit. With this free breathing valve, if a patientattempts to spontaneously breathe then the free breathing valve actuatesenabling the user to pull in air from the surrounding environment. Forventilators that include free breathing valves, check valves included inthe patient breathing circuit can defeat the purpose of this safetyfeature and may not be used with such ventilators.

In exemplary embodiments, to reduce and/or prevent interference withfree breathing valve 302, check valve 202 and/or an additional checkvalve can be placed at, and/or be in fluid communication with, injectormodule 107, therapeutic gas inlet 110, and/or conduit 105. For example,at least one check valve 304, alone and/or in combination with checkvalve 202, can be located at therapeutic gas inlet 110 of injectormodule 107.

In exemplary embodiments, to address at least some of the abovephenomena (e.g., false NO flow, etc.) and/or provide additionalbenefits, NO flow can be measured upstream of the control valve. In thisconfiguration (e.g., the NO flow sensor upstream of the control valve),when the control valve is closed, the NO flow sensors exposure to atleast some of the above phenomena can be substantially reduced and/oreliminated For example, to reduce and/or eliminate the NO flow sensorsexposure to at least some of the above phenomena, NO flow sensor 115 canbe located upstream of valve 109. In at least some instances, NO flowsensor 115, whether upstream or downstream of valve 109, can be used todetermine whether valve 109 is working properly and/or whether flow isleaking past valve 109. For example, if flow beyond what is anticipatedis detected by NO flow sensor 115 then this can be indicative of a leakin valve 109.

In exemplary embodiments, to address at least some of the abovephenomena (e.g., false NO flow, etc.) and/or provide additionalbenefits, the NO delivery conduit (e.g., conduit 105) can have asubstantially small cross-sectional diameter. For example, the NOdelivery conduit (e.g., conduit 105) can have an internalcross-sectional diameter of about 1/32 of an inch to about ¼ of an inch.For another example, the NO delivery conduit (e.g., conduit 105) canhave an internal cross-sectional diameter of about ⅛ of an inch. Thecross-section can be selected to substantially reduce the compressiblevolume in the NO delivery conduit, for example, so that the oscillatorysignal detected by the flow sensor may be substantially reduced and/oreffectively eliminated. In at least some instances, the cross-sectioncan be selected to substantially increase resistance to flow so thatpressure changes and/or oscillations affiliated with a high frequencyventilator may not be great enough to overcome the increased resistanceto flow and/or so that propagation of the pressure changes and/oroscillations can be substantially reduced and/or eliminated, forexample, prior to reaching the NO flow sensor (e.g., NO flow sensoraffiliated with the delivery system, etc.). In at least someembodiments, the internal cross-sectional diameter of the NO deliveryconduit (e.g., conduit 105) can be the same cross-sectional diameterwhether internal or external to system 100 and/or NO delivery conduit(e.g., conduit 105) can be the same cross-sectional diameter at leastonce downstream of the flow control valve.

Referring to FIGS. 4A-4B, exemplary injector modules are illustrativelydepicted that can address at least some of the above phenomena (e.g.,false NO flow, etc.) and/or provide additional benefits. Injector module400 can include a first end 404 and a second end 406 that can be coupledto the inspiratory limb of the patient breathing circuit. At first end404 and second end 406 there can be a first opening and a secondopening, respectively, in the body of injector module 400 enabling fluidflow (e.g., breathing gas, etc.) through the injector module. Injectormodule 400 can also include a communication port 408 enablingcommunication of information between the injector module (and anyaffiliated components) and the nitric oxide delivery system (e.g., fluidand/or pneumatic communication, electrical and/or digital communication,etc.). Systems and methods of the present invention may use thisinformation to, for example, address at least some of the abovedescribed phenomena and/or provide additional benefits. Further,injector module 400 can include a therapeutic gas inlet 410 that canreceive therapeutic gas from the nitric oxide delivery system and/or canenable injection of therapeutic gas into breathing gas flowing throughthe injector module.

In exemplary embodiments, injector modules of the current invention caninclude and/or be in fluid communication with one or more bi-directionalNO flow sensors, for example, to address at least some of the abovephenomena (e.g., false NO flow, etc.) and/or provide additionalbenefits. For example, injector module 400 can include and/or be influid communication with one or more bi-directional nitric oxide (NO)flow sensors 412. Bi-directional NO flow sensor 412 can be located atand/or be in fluid communication with therapeutic gas inlet 410 and/orbi-directional NO flow sensor 412 can measure flow through the NOdelivery conduit (e.g., conduit 105 illustrated in FIG. 1 ) to injectormodule 400 and/or to the inspiratory limb of the patient breathingcircuit. Further, bi-directional NO flow sensor 412 can be used as afeedback control signal for NO delivery and/or can be used to monitorthe flow and/or quantity of NO gas being delivered into the patientbreathing circuit. For example, flow measurements from bi-directional NOflow sensor 412 can be compared against flow measurements from flowsensor 115 to detect NO leaks. This can result in more accurate dosingand/or can reduce the risk of nitric oxide leaking into the surroundingenvironment.

In at least some embodiments, although illustrated as being located attherapeutic gas inlet 410, bi-directional NO flow sensor 412 can be inany location in fluid communication with NO being delivered to theinjector module. For example, bi-directional NO flow sensor 412 can belocated at the nitric oxide delivery system and/or at any point that canbe in fluid communication with the NO delivery conduit (e.g., conduit105 illustrated in FIG. 1 ). For another example, bi-directional NO flowsensor 412 can replace, or be used in conjunction with, NO flow sensor115 (illustrated in FIGS. 1-3 ).

In at least some embodiments, two or more bi-directional NO flow sensorscan be located at and/or be in fluid communication with therapeutic gasinlet 410. For example, one or more bi-directional NO flow sensors canbe located at therapeutic gas inlet 410 and/or one or morebi-directional NO flow sensors can be in fluid communication withtherapeutic gas inlet 410. Two or more bi-directional NO flow sensorscan, for example, enable flow measurements of NO being delivered viainjection module 400 for a substantially wide range of flow rates.

In exemplary embodiments, bi-directional NO flow sensor 412 can be anysensor capable of measuring flow in both the forward and reversedirection For example, bi-directional flow sensor 119 can be a thermalmass flow meter (sometimes called a thermal dispersion flow meter);pressure-based flow meter; optical flow meter; electromagnetic,ultrasonic, and/or Coriolis flow meter; laser Doppler flow meter, and/orany flow meter that provides a response time of less than about twomilliseconds and has a range of not more than +−10 SLPM. Exemplarylimits for the reverse flow may be −10, −9, −8, −7, −6, −5, −4, −3,−2.5, −2, −1.5, −1, −0.75, −0.5, −0.4, −0.3, −0.2 or −0.1 SPLM.Similarly, exemplary limits for the forward flow may be 10, 9, 8, 7, 6,5, 4, 3, 2.5, 2, 1.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2 or 0.1 SPLM. In atleast some instances, bi-directional flow sensor 119 can be apressure-based flow meter (e.g., differential pressure sensor type flowmeter, etc.) and/or fluid and/or pneumatic communication can be providedvia communications port 408.

In exemplary embodiments, bi-directional NO flow sensor 412 can be incommunication with the nitric oxide delivery system, for example, viacommunication port 408. This can allow flow information to becommunicated to the nitric oxide delivery system, which can be used bythe nitric oxide delivery system for NO delivery and/or monitoring.Using this bi-directional flow information nitric oxide delivery systemcan more accurately deliver and/or monitor NO.

In exemplary embodiments, systems and methods of the present inventioncan use techniques (e.g., algorithms, user input, etc.) to determinewhether a high frequency ventilator may be being used. Further, inexemplary embodiments, if determined that a high frequency ventilatormay be being used, systems and methods of the present invention can usetechniques (e.g., algorithms, user input, etc.) to compensate for atleast some of the surprising phenomena (e.g., false NO flow, etc.)and/or affects that may, at times, occur when wild stream blendingtherapeutic gas into breathing gas in a breathing circuit affiliatedwith a high frequency ventilator and/or provide additional benefits.These techniques can, at times, use information from at least thetherapeutic gas flow sensor, such as, NO flow sensor 115 (e.g., that maymeasure flow in one direction, etc.), NO flow sensor 412 (e.g., that maymeasure flow in more than one direction, etc.) and/or any flow sensor influid communication with, the injector module, the therapeutic gasinlet, and/or the NO conduit.

Systems and methods of the present invention can determine whether ornot therapeutic gas (e.g., NO) may be being delivered into a breathingcircuit affiliated with a high frequency ventilator using any reasonabletechnique, such as, but not limited to, user input (e.g., user inputinformation to the nitric oxide delivery system), detection (e.g.,detection algorithm by the nitric oxide delivery system), signalrecovery, and/or any combination and/or further separation thereof,direct communication with the ventilator, to name a few. For example,the nitric oxide delivery system can allow a user to input that NO maybe being delivered into a breathing circuit affiliated with a highfrequency ventilator. For another example, the nitric oxide deliverysystem can detect (e.g., without user input, with some user input, etc.)that NO may be being delivered into a breathing circuit affiliated witha high frequency ventilator using, for example, detection and/or signalrecovery techniques.

In exemplary embodiments, if determined that a high frequency ventilatormay be being used, systems and methods of the present invention cancompensate for at least some of the surprising phenomena (e.g., false NOflow phenomena, etc.), effects affiliated with high frequencyventilators, and/or provide additional benefits using any reasonabletechnique, such as, but not limited to, filtering, using reductiontechniques, any combination and/or further separation thereof, and/orusing any process capable of compensating for high frequency ventilatorgenerated information affiliated with NO flow information, changing theNO delivery control algorithm such that it may not respond to highfrequency oscillations, electrical filtering, digital filtering, the NOflow sensor being located upstream of the flow control valve,substantially small diameter NO injection tubing being used, and/orpneumatic filtering, to name a few. By way of example, systems andmethods of the present invention can consider high frequency ventilatorgenerated information as noise and can use any reasonable technique toremove this noise from the NO flow information (e.g., information fromthe NO flow sensor). Techniques can include, but are not limited to,linear filters, nonlinear filters, statistical signal processing, noisegating, and/or any combination and/or further separation thereof, toname a few.

To ease understanding, at least some exemplary detection and/or signalrecovery techniques and/or exemplary compensation techniques aredisclosed herein. It will be understood that other techniques can beused. Further, it will be understood that techniques disclosed hereinare merely for ease of understanding and are in no way meant to beexhaustive.

By way of example, to determine whether NO may be being delivered into abreathing circuit affiliated with a high frequency ventilator, systemsand methods of the present invention can identify pressure and/or flowinformation indicative of use of high frequency ventilator systems. Inat least some instances pressure and/or flow information from an NO flowsensor, such as, flow sensor 115 (illustrated in FIGS. 1-3 ) and/orbi-directional NO flow sensor 412 (illustrated in FIGS. 4A-4B) can beanalyzed (e.g., by the nitric oxide delivery system) to determine if ahigh frequency ventilator may be being used. For example, informationfrom the NO flow sensor may be analyzed against expected informationfrom the NO flow sensor and/or actual NO flow information may bediscerned from high frequency ventilator generated flow information thatdistracts from the actual NO flow information. By way of example,information from NO flow sensor indicative high frequency unexpectedforward and/or reverse flow and/or pressure, high frequency unexpectedforward flow and/or pressure, high frequency unexpected zero and/orforward and/or reverse flow, to name a few, can be analyzed againstexpected flow information.

Referring to FIGS. 5A-5C graphical representation of information from anNO flow sensor are illustratively depicted to demonstrate at least oneexemplary technique for determining if a high frequency ventilator maybe being used. It will be understood that information from the NO flowsensor may be in the form of a current, voltage, and/or any other formof information that may be indicative of a flow and/or pressure. Forease, the indicative flow rate is illustratively depicted. This ismerely for ease and is in no way meant to be a limitation.

Referring to FIG. 5A, plot 502 illustratively depicts exemplary expectedinformation from the NO flow sensor for a desired flow rate of 10ml/min, for example, when delivering NO into a breathing circuit thatmay not be affiliated with a high frequency ventilator. Plot 502, asillustrated, can be considered to be a substantially flat line as plot502 illustrates the expected information from the NO flow sensor for aconstant flow rate (e.g., constant flow rate of 10 ml/min). Of courseshould the flow rate not be constant the plot would correspondaccordingly. For example, a constant flow rate may be provided for aportion of a patient's breathing cycle and then varied for anotherportion of the patient's breathing cycle. For ease of understanding aconstant flow rate is illustrated. This is merely for ease and is in noway meant to be a limitation.

Referring to FIG. 5B, plot 504 illustratively depicts exemplary highfrequency ventilator expected information from the NO flow sensor for anexemplary flow rate of 0 ml/min. Plot 504, as illustrated, can beconsidered to be a non-linear shape (e.g., sinusoidal, etc.) as plot 504illustrates information from the NO flow sensor for vibrations orpressure oscillations, for example, that may be at least partiallygenerated by the high frequency ventilator.

Referring to FIG. 5C, plot 506 illustratively depicts exemplary actualinformation from the NO flow sensor for a flow rate of 10 ml/min whendistorted by vibrations or pressure oscillations. Plot 506 can, attimes, be considered to be the distorted sum of the exemplary expectedinformation from the NO flow sensor for a desired flow rate of 10 ml/min(e.g., plot 502 in FIG. 5A) combined with exemplary information from theNO flow sensor indicative of high frequency ventilator generatedvibration or pressure oscillations. These distortions can cause thenitric oxide delivery system to believe flow may be being delivered at arate other than the desired constant flow rate of 10 ml/min (even thoughthese distortions may be indicative of false NO flow and not the actualNO flow).

Problematically, in response to this incorrect flow information, the NOdelivery system may adjust the flow of gas to the breathing circuit toattempt to deliver at the desired flow rate. As this new flow rate maybe based on distortions and not the actual flow rate this adjusted flowrate can cause the actual delivery of NO into the breathing circuit tonot be at the desired flow rate.

Even further compounded the above problem, as the NO delivery systemattempts to adjust the flow of gas to the breathing circuit to attemptto deliver at the desired flow rate, the delivery valve(s) (e.g., valve109, etc.) may be actuated (e.g., opened, closed, partially opened,partially closed, etc.). This valve actuation may cause interaction ofthe valve components which can, in at least some instances, cause atleast a lag time in delivery. By way of example, when attempting toadjust the flow (which may not need to be adjusted) the valve may beclosed and then reopened requiring the valve to overcome forcesaffiliated with static friction and/or dynamic friction. These forcesmay not be constant (e.g., more force may be required to overcome staticfriction than dynamic friction) which can cause a lag in valve actuationand/or NO delivery. In exemplary embodiments, using techniques disclosedherein the quantity of times that the system attempts to adjust the NOflow may be reduced and/or eliminated. This can result in reducing theincidence of the above disclosed problem. Further, this can, in at leastsome instances, result in increased accuracy of NO delivery andmonitoring and/or under delivery of therapeutic gas into the breathinggas can be avoided and/or reduced.

Addressing at least the above, in exemplary embodiments, systems andmethods of the present invention can use techniques (e.g., algorithms,user input, etc.) to more effectively actuate valves and/or compensatefor forces that may affect valve actuation such as, but not limited to,static friction, dynamic friction, and/or valve component interactions,to name a few. For example, systems and methods of the present inventionmay, at times, identify, factor in, and/or compensate for the amount offorce needed to overcome various forces (e.g., static friction, dynamicfriction, etc.).

Still referring to FIGS. 5A-5C, following the above example, to detectuse of a high frequency ventilator, systems and methods of the presentinvention can analyze the actual information from the NO flow sensoragainst the expected information from the NO flow sensor for a desiredflow rate. For example, when delivering 10 ml/min of NO the nitric oxidedelivery system analyzes actual information from the NO flow sensor(e.g., as illustrated in plot 506 of FIG. 5C) against expectedinformation from the NO flow sensor (e.g., as illustrated in plot 502 ofFIG. 5A) and identifies substantial deviation then the nitric oxidedelivery system can determine that NO may be being delivered into abreathing circuit affiliated with a high frequency ventilator.Substantial deviations may be identifiable as flow oscillations of lessthan about 80 oscillations per minute can be expected as conventionalventilator breath rates can be less than about 80 breaths per minutewhile oscillations affiliated with high frequency ventilators can be onthe magnitude of hundreds of oscillations per minute.

Still following the above example, with use of a high frequencyventilator being detected, systems and methods of the present inventioncan compensate for the information generated by at least the highfrequency ventilator. For example, the nitric oxide delivery system canfilter out information indicative of high frequency ventilator generatedvibration or pressure oscillations from the information from the NOflow. With this high frequency generated information filtered out, thenitric oxide delivery system can deliver the correct dose of NO to thepatient.

Compounding the above challenges, it has been found that at least theabove false NO flow phenomena can, at times, be more likely forsubstantially small flow rates (e.g., less 100 ml/min). Further, atleast the above phenomena can distort the flow information to a largeenough degree that zero flow and/or negative flow may be believed to beoccurring. Problematically, substantially small flow rates may bebeneficial and/or required to deliver the desired dose of NO to apatient. Failure to detect and/or compensate for at least the abovephenomena may, at times, lead to delivery of dosing to a patient thatmay not be the desired therapeutic dose and, this may, at times, impactefficacy.

In exemplary embodiments, smaller distortions may be compensated forusing information from a mono-directional and/or bi-directional flowsensor and/or larger distortions may, at times, require usinginformation from a bi-directional flow sensor and/or may requireadditional techniques. Referring back to FIG. 5C, plot 506 shows adistortion of the desired 10 ml/min flow as being between 5 ml/min and15 ml/min. Under this example, detection and/or compensation for falseNO flow may be accomplished by a mono-directional flow sensor and/orbi-directional flow sensor, for example, as the flow rate does not gobelow 0 ml/min. However, in exemplary embodiments, for distortions ofthe desired flow below 0 ml/min detection and/or compensation can bemore complicated and/or require a bi-directional flow sensor.

For example, referring to FIG. 6A, plot 606 shows a 10 ml/min desiredflow exhibiting 15 ml/min distortions (e.g., plot 606 distorts between25 ml/min and −5 ml/min) such that the desired flow distorts below 0ml/min between points 608 and 610. This negative region of plot 606between points 608 and 610 can be considered to be indicative of falseNO flow in the reverse direction. As this flow may be considered to bein the reverse direction, using bi-directional flow sensor informationplot 606 may appear as shown in FIG. 6A while using mono-directionalflow sensor information plot 606 may appear as shown in FIG. 6B (e.g.,as no flow, 0 ml/min flow, etc.) and/or as shown in FIG. 6C (e.g., as anequal and opposite positive flow, as positive values for the negativevalues).

In exemplary embodiments, a bi-directional flow sensor and/orinformation from a bi-directional flow sensor may be used to detectand/or compensate for substantially small flows and/or distortionsindicative of flow below 0 ml/min. Information from a bi-directionalflow sensor may be used to detect use of a high frequency ventilatorand/or may be used to compensate for information from the NO flow sensorthat may be indicative of high frequency ventilator generated vibrationor pressure oscillations using any reasonable technique such as, but notlimited to, any of the techniques disclosed herein.

Referring to FIGS. 6B-6C, in exemplary embodiments, a mono-directionalflow sensor and/or information from a mono-directional flow sensor maybe used to detect and/or compensate for substantially small flows and/ordistortions indicative of flow below 0 ml/min using any reasonabletechnique, such as, but not limited to, interpolation, curve fitting,and/or regression analysis, to name a few.

For example, to detect use of a high frequency ventilator using amono-directional flow sensor and/or information from a mono-directionalflow sensor, systems and methods of the present invention can analyzethe actual information from the NO flow sensor against the expectedinformation from the NO flow sensor for a desired flow rate and mayconsider distortions above the expected information from the NO flowsensor. Using this technique, system and methods of the presentinvention may detect use of a high frequency ventilator by onlyconsidering positive values above the expected information from the NOflow sensor using any reasonable technique such as, but not limited to,any of the techniques disclosed herein.

Following the above example, with use of a high frequency ventilatorbeing detected using a mono-directional flow sensor and/or informationfrom a mono-directional flow sensor, systems and methods of the presentinvention can compensate for information that may be indicative of highfrequency ventilator generated vibration or pressure oscillations usingany reasonable technique such as, but not limited to, any of thetechniques disclosed herein. For example, for the region between points608 and 610 of plot 606 (as shown in FIG. 6B), systems and methods ofthe present invention can interpolate the missing plot information andcompensate for the distortions (e.g., distortions actually seen and/orinterpolated distortions) using any reasonable technique such as, butnot limited to, any of the techniques disclosed herein. For anotherexample, for the region between points 608 and 610 of plot 606 (as shownin FIG. 6C), systems and methods of the present invention can invertthese values (e.g., consider the positive values as negative values) andcompensate for the distortions (e.g., distortions actually seen and/orinverted distortions) using any reasonable technique such as, but notlimited to, any of the techniques disclosed herein.

Those skilled in the art will readily recognize numerous adaptations andmodifications which can be made to the therapeutic gas delivery systemsand method of delivering a pharmaceutical gas of the present inventionwhich will result in an improved method and system for introducing aknown desired quantity of a pharmaceutical gas into a patient, yet allof which will fall within the scope and spirit of the present inventionas defined in the following claims. Accordingly, the invention is to belimited only by the following claims and their equivalents.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments,” “exemplary embodiment,”“exemplary embodiments,” and/or “an embodiment” means that a particularfeature, structure, material, or characteristic described in connectionwith the embodiment is included in at least one embodiment of theinvention. Thus, the appearances of the phrases such as “in one or moreembodiments,” “in certain embodiments,” “in one embodiment,” “exemplaryembodiment,” “exemplary embodiments,” and/or “in an embodiment” invarious places throughout this specification are not necessarilyreferring to the same embodiment of the invention. Furthermore, theparticular features, structures, materials, or characteristics can becombined in any suitable manner in one or more embodiments.

It will be understood that any of the steps described can be rearranged,separated, and/or combined without deviated from the scope of theinvention. For ease, steps are, at times, presented sequentially. Thisis merely for ease and is in no way meant to be a limitation.

Further, it will be understood that any of the elements and/orembodiments of the invention described can be rearranged, separated,and/or combined without deviated from the scope of the invention. Forease, various elements are described, at times, separately. This ismerely for ease and is in no way meant to be a limitation.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A method of delivering nitric oxide gas to a patient in need thereof, the method comprising: providing, through at least one control valve of a nitric oxide delivery system, a flow of nitric oxide gas to an injector module configured to inject the nitric oxide gas into a breathing gas in an inspiratory limb of a breathing circuit affiliated with a high frequency ventilator or ventilation techniques which provide reverse and/or oscillations in inspiratory pressure or flow; measuring, using at least one NO flow sensor, NO flow, wherein the at least one NO flow sensor is in fluid communication with a therapeutic gas inlet of the injector module; receiving, using a control system in communication with the at least one NO flow sensor, flow information from the at least one NO flow sensor; and delivering the nitric oxide gas to the patient.
 2. The method of claim 1, wherein the injector module has an injector body having a first opening and a second opening, the first opening and the second opening being configured to couple the injector module to the inspiratory limb of the breathing circuit enabling the breathing gas in the breathing circuit to flow through the first opening and the second opening.
 3. The method of claim 2, wherein the therapeutic gas inlet is in the injector body, the therapeutic gas inlet being configured to receive the flow of the nitric oxide gas and enable injection of the nitric oxide gas into the injector module, and in turn into the breathing gas in the inspiratory limb of the breathing circuit.
 4. The method of claim 1, wherein the control system is operable to: (i) detect use of the high frequency ventilator; (ii) identify the flow information as missing and interpolate the missing flow information; and/or (iii) identify the flow information as reverse flow.
 5. The method of claim 1, wherein the therapeutic gas inlet receives the flow of nitric oxide gas from a nitric oxide source, via a conduit.
 6. The method of claim 5, wherein the nitric oxide source is a cylinder storing NO or an NO generator.
 7. The method of claim 6, further comprising generating the nitric oxide gas by reaction of a NO-releasing agent with a reductant using the NO generator.
 8. The method of claim 7, wherein the NO-releasing agent is nitrogen dioxide and the reductant is ascorbic acid.
 9. The method of claim 1, further comprising monitoring the flow information, using the control system, to ensure that a desired dose of NO is delivered into the injector module, and in turn into the breathing gas in the inspiratory limb of the breathing circuit.
 10. The method of claim 1, furthering comprising monitoring the flow information, using the control system, to ensure a desired does of NO is not under delivered and/or under dosed.
 11. The method of claim 1, further comprising opening or closing a check valve that is one or more of (i) in fluid communication with the therapeutic gas inlet of the injector module and (ii) is integral to the injector module.
 12. The method of claim 1, wherein the at least one NO flow sensor is at least one bi-directional flow sensor.
 13. The method of claim 12, wherein the at least one bi-directional flow sensor is a thermal mass flow meter or a thermal dispersion flow meter.
 14. The method of claim 1, wherein the inspiratory limb is also an expiratory limb in the breathing circuit.
 15. The method of claim 1, wherein the NO flow sensor is downstream of the control valve in the nitric oxide delivery system.
 16. The method of claim 1, wherein the control valve is upstream of the NO flow sensor in the nitric oxide delivery system.
 17. The method of claim 1, further comprising receiving the flow of nitric oxide gas at the therapeutic gas inlet via a conduit, wherein the conduit has one or more of (i) an internal cross-sectional diameter of about 1/32 of an inch to about ¼ of an inch and (ii) an internal portion within the nitric oxide delivery system and an external portion outside the nitric oxide delivery system, the internal portion of the conduit having a cross-sectional diameter that is substantially the same as a cross-sectional diameter of the external portion of the conduit.
 18. The method of claim 1, further comprising: measuring, using at least a second NO flow sensor, NO flow, wherein the second NO flow sensor is in fluid communication with the therapeutic gas inlet and in communication with the control system, receiving, at the control system, flow information from the second NO flow sensor; and detecting, using the control system, a leak when the flow information from the NO flow sensors does not match.
 19. The method of claim 18, further comprising increasing the flow of nitric oxide gas if a leak is detected.
 20. A method of delivering nitric oxide gas to a patient in need thereof, the method comprising: providing, through a conduit and at least one control valve of a nitric oxide delivery system, a flow of nitric oxide gas to a therapeutic gas inlet of an injector module from a nitric oxide gas source, wherein the nitric oxide is injected into a breathing gas in an inspiratory limb of a breathing circuit affiliated with a high frequency ventilator or ventilation techniques which provide reverse and/or oscillations in inspiratory pressure or flow; measuring, using at least one bi-directional NO flow sensor, NO flow in a forward direction and in a reverse direction through the therapeutic gas inlet, wherein the at least one bi-directional NO flow sensor is in fluid communication with the therapeutic gas inlet; receiving, using a control system in communication with the at least one bi-directional NO flow sensor, bi-directional flow information; and delivering the nitric oxide gas to the patient.
 21. The method of claim 20, wherein the injector module has an injector body having a first opening and a second opening, the first opening and the second opening being configured to couple the injector module to the inspiratory limb of the breathing circuit enabling the breathing gas in the breathing circuit to flow through the first opening and the second opening.
 22. The method of claim 21, wherein the therapeutic gas inlet is in the injector body, the therapeutic gas inlet being configured receive the flow of the nitric oxide gas and enable injection of the nitric oxide gas into the injector module, and in turn into the breathing gas in the inspiratory limb of the breathing circuit.
 23. The method of claim 20, wherein the bi-directional flow information comprises at least forward flow information and reverse flow information.
 24. The method of claim 20, wherein the nitric oxide source is a cylinder storing NO or an NO generator.
 25. The method of claim 24, further comprising generating the nitric oxide gas by reaction of a NO-releasing agent with a reductant using the NO generator.
 26. The method of claim 25, wherein the NO-releasing agent is nitrogen dioxide and the reductant is ascorbic acid.
 27. The method of claim 20, further comprising monitoring the flow information, using the control system, to ensure that a desired dose of NO is delivered into the injector module, and in turn into patient breathing gas in the inspiratory limb of the breathing circuit.
 28. The method of claim 20, further comprising monitoring the flow information, using the control system, to ensure that a desired dose of NO is not under delivered and/or under dosed.
 29. The method of claim 20, further comprising opening or closing a check valve that is one or more of (i) in fluid communication with the therapeutic gas inlet of the injector module and (ii) is integral to the injector module.
 30. The method of claim 20, wherein the at least one bi-directional flow sensor is a thermal mass flow meter or a thermal dispersion flow meter.
 31. The method of claim 20, wherein the inspiratory limb is also an expiratory limb in the breathing circuit.
 32. The method of claim 20, wherein the NO flow sensor is downstream of the control valve in the nitric oxide delivery system.
 33. The method of claim 20, wherein the control valve is upstream of the NO flow sensor in the nitric oxide delivery system.
 34. The method of claim 20, wherein the conduit has one or more of (i) an internal cross-sectional diameter of about 1/32 of an inch to about ¼ of an inch and (ii) an internal portion within the nitric oxide delivery system and an external portion outside the nitric oxide delivery system, the internal portion of the conduit having a cross-sectional diameter that is substantially the same as a cross-sectional diameter of the external portion of the conduit.
 35. The method of claim 20, further comprising: measuring, using at least a second bi-directional NO flow sensor, NO flow, wherein the second bi-directional flow sensor is in fluid communication with the therapeutic gas inlet and in communication with the control system, receiving, at the control system, flow information from the second bi-directional NO flow sensor; and detecting, using the control system, a leak when the flow information from the NO flow sensors does not match.
 36. The method of claim 35, further comprising increasing the flow of nitric oxide gas if a leak is detected. 